The annual ASH (American society of hematology) meeting will take place next month in New Orleans. Based on the abstracts that were released 2 weeks ago, it seems that after 2 phenomenal years of introducing novel mechanisms, this year’s meeting is going to be more on the evolving landscape in each segment (Btk/PI3K inhibitors, antibody drug conjugates, myelofibrosis, CD38 antibodies, chimeric antigen receptors etc.).
Below are my top picks.
Infinity – Still trying to differentiate IPI-145
Infinity (INFI) had a great meeting last year at ASH 2012 but investor sentiment took a 180 degree turn in 2013 and the stock is down 70% from its peak in April. Although everybody agrees Infinity’s isoform-selective PI3K inhibitor, IPI-145, is active across multiple indications, there is skepticism regarding competition as well as safety concerns.
At this year’s meeting, Infinity will present data for IPI-145 in CLL, indolent NHL and T cell lymphomas. The CLL data set will be at the center of attention, as it will be compared to competing drugs, particularly Gilead’s (GILD) idelalisib (also a PI3K inhibitor) and Pharmacyclics'(PCYC) ibrutinib (brand name Imbruvica).
In order to do regain the market’s trust Infinity must convince investors that:
1- There is a place for PI3K inhibitors alongside ibrutinib
2- IPI-145 is truly differentiated from Gilead’s idelalisib
3- There is no increased rate of infections with IPI-145 compared to other drugs
According to the abstract, response rate (52-53%) was in line with the prior update in June (55%), which is not surprising given that the abstracts were submitted in July. Actual data at ASH will include more patients, higher doses and longer follow up.
The response rate continues to look numerically better than idelalisib (~40%) and lower than ibrutinib (~70%). In order to differentiate IPI-145 from idelalisib, response rate needs to improve to 60%. This, together with quicker onset of response and potentially better CR rate, should be sufficient to position IPI-145 as a best in class PI3K inhibitor.
The company hopes that with more follow up, response rate will increase as a result of longer treatment duration that may lead some of the nodal responses to convert to full blown responses. This was also the case with Idelalisib which had an initial response rate of 26%. To date, this has not materialized but the constant addition of new patients with limited follow up may have contributed to that.
From a safety perspective, Infinity has to show a comparable risk of respiratory and infectious adverse events. The company implemented preventive anti-infective treatment earlier this year, so it will be interesting to see whether rate of infections decrease in newly recruited patients.
A small cohort of ibrutinib-failures will also be presented. Any signs of activity in this subset could be critical for IPI-145’s positioning in CLL. Responses may create an important near term commercial opportunity (albeit relatively small) and a validation for PI3K inhibitors in general.
There are multiple isoform-selective PI3K inhibitors in development. These include a 2nd-generation molecule from Gilead (GS-9820), Amgen’s (AMGN) AMG319, Incyte’s (INCY) INCB40093 and TG Therapeutics’ (TGTX) TGR-1202. Some of these compounds will have data at ASH.
According to the abstract, GS-9820 demonstrated early signs of activity with no liver toxicity. AMG319 has early but promising activity, with lymph node reductions across all 21 CLL patients and what appear to be responses in 7 patients. Importantly, all 7 received a higher dose. No activity was observed with TG therapeutics’ TGR-1202, but the company will report data with higher doses at ASH. It is important to note that the drugs above are only delta-selective as opposed to IPI-145, which is a gamma/delta inhibitor.
The fact other companies are pursuing PI3K inhibitors is encouraging as it implies these companies still believe in the relevance of this class of drugs in the ibrutinib era.
Pharmacyclics – Ono as an emerging competitor
Pharmacyclics’ Imbruvica is still the undisputed leader in B cell malignancies, with a high likelihood of becoming a $5B+ drug. Fortunately for Pharmacyclics, there are very few other Btk inhibitors in development, the most advanced being Celgene’s (CELG) CC-292, which could not replicate ibrutinib’s strong efficacy. At ASH, Celgene will present updated results that look better but the drug’s clinical profile (safety/efficacy) still looks inferior. This explains Celgene’s strategy to pursue CC-292 in combinations in contrast to Imbruvica, which was initially pursued as monotherapy.
Japan-based Ono will have results for its Btk inhibitor, which appears promising based on preliminary efficacy mentioned in the abstracts. In CLL, 7/10 patients had a nodal response including 2 PRs whereas 3/6 MCL patients experienced a PR. Even if Ono’s Btk inhibitor proves to be comparable to ibrutinib, it still trails in development by at least 2 years. As ibrutinib will become approved in all the major indications within 1-2 years, Ono will have to run comparative trials to demonstrate its drug’s non-inferiority. In some indications, these trials will take years to read out.
Incyte – Focus on competitive landscape
At this year’s ASH, investor focus will be more on potential competition rather than data for Jakafi. Incyte (INCY) will present updated survival data from its pivotal trials, which continue to show a clear separation of the curves with good statistical values. Hazard ratios deteriorated a bit but the signal is still impressive given the fact both trials were not designed to assess survival and the cross-over of patients from the control arm to Jakafi.
Activity for Incyte’s selective Jak1 (INCB39110) inhibitor in myelofibrosis (MF) appears underwhelming which implies that Jak2 inhibition is required for clinical improvement. This should not have a major impact on this program’s prospects as the main value is still in autoimmune diseases, particularly in RA. The hematologic side effects are concerning and look more prevalent than other Jak1-selective inhibitors but this may be related to the disease itself rather than the drug. As a reminder, Galapagos’ Jak1-selective inhibitor was partnered with Abbvie (ABBV) in a huge deal that included a $150M upfront payment.
Sanofi (SNY) will present phase III data for its Jak1/2 inhibitor, fedratinib, which is Jakafi’s most advanced competitor. Fedratinib demonstrated good activity measured by spleen volume and symptom relief but appears to have more safety issues than Jakafi. Given a better overall clinical profile, it looks like Jakafi will remain the dominant Jak inhibitor for at least 2 more years. Next challenge will be from Gilead’s momelotinib, which just started a head to head phase III vs. Jakafi. The trial is designed to show superiority in terms of anemia with a comparable effect on spleen size and symptoms.
Geron – a potential disease modifying agent for MF
Geron (GERN) will have an intriguing data set for imetelstat in MF, which is already spurring controversy. Geron is trying to position imetelstat as the first disease-modifying MF drug based on promising effect in the bone marrow. According to the abstract, of the 18 patients who were on the drug for at least 3 months, 4 had a complete response according to bone marrow biopsies and blood tests. This activity is not seen with Jakafi or other Jak inhibitors, which are viewed more as symptomatic anti-inflammatory drugs.
Imetelstat’s effect is very intriguing and suggests the drug may treat the underlying disease (Fibrosis in the bone marrow caused by aberrant cell growth), rather than its symptoms. Still, results are preliminary and a lot of information is missing (response durability, reduction in spleen size, constitutional symptoms), so the updated results will be crucial in understanding the drug’s potential in MF. Imetelstat’s safety profile and the fact it has to be given IV are 2 additional issues.
Interestingly, imetelstat’s data set comes from Mayo Clinic’s Ayalew Tefferi, the same clinician who did the initial trial for YM Biosciences’ (now part of Gilead) momelotinib (CYT387). At the 2011 and 2012 ASH meetings, momelotinib’s unexplained anemia effect led some to speculate it may displace Incyte’s Jakafi although most were skeptical. This year, Tefferi comes to ASH with another potential “Jakafi-killer” but this time with a potential disease modifier.
Seattle Genetics – Internal and partnered pipeline advance
For Seattle Genetics (SGEN), this year’s ASH will be all about DLBCL, an aggressive lymphoma subtype which represents a highly unmet need with no meaningful advances since 2006 (Rituxan’s approval). Investigators will present updated phase II for the company’s Adcteris and for Genentech’s CD22 and CD79b antibody drug conjugates (ADCs).
According to the abstracts, all 3 ADCs have good activity in DLBCL with response rates of:
1- 40% (16% CR) for Adcetris
2- 41% (17% CR) for CD22 ADC
3- 48% (10% CR) for CD79b ADC
Adcetris appears to have the best clinical profile with a high number of CRs, good response durability (8+ months) and a manageable safety profile in a truly refractory patient population although less heavily pretreated. Obviously, this may change at ASH with updated results for the 3 programs.
There is still open questions regarding Adcetris in DLBCL, including the importance of CD30 expression for patient selection (initially targeted CD30+ DLBCL but activity is seen also with minimal CD30 expression) and the approval route in DLBCL. Some believe Adcetris’ activity may be sufficient for compendia listing or even accelerated approval.
Amgen will also present data for blinatumomab, a bispecific CD3XCD19 antibody, in DLBCL. The abstract discloses responses in 4 out of 7 patients (57%) with limited follow up.
Adcetris will also have updated results in CTCL, where response rate increased to 71% (was 65% at the last update).
Early data for SGN-19A, an anti-CD19 ADC, will also be presented. The abstract includes only lower doses and a complete response in ALL. It remains to be seen whether SGN-19A is differentiated from other CD19 antibodies and ADCs.
Genmab – Main focus still on Arzerra, but should be on daratumumab
Genmab’s (GEN.CO) shares have come under pressure after data release for Roche’s Gazyva (GA-101) in CLL. Gazyva, a glyco-engineered CD20 antibody is the biggest threat to Genmab/GSK’s CD20 antibody, Arzerra. Both companies will present phase III results in 1st line CLL.
Gazyva’s abstract reveals impressive activity and most importantly for Roche, clear superiority over Rituxan. Gazyva led to almost a year’s difference (26.7 vs. 15.2 months) in PFS, which is even more impressive given the fact that the control arm received chemotherapy and Rituxan. CR (21% vs. 7%) and minimal residual disease (29.4% vs. 2.5%) rates were also significantly better for Gazyva.
Arzerra’s phase III evaluated Arzerra+chemotherapy to chemotherapy alone and generated PFS and CR values that appear numerically inferior (cross trial comparison). Arzerra demonstrated a PFS of 22.4 months and a CR rate of 12%. Hazard ratio also appears inferior to Gazyva’s past performance versus chemotherapy alone (0.57 vs. 0.16).
Genmab claims that the market’s conclusion about Gazyva’s superiority is not based on an apples-to-apples comparison. With respect to PFS and CR, Gazyva’s results are based on investigator assessment while Arzerra’s data are based on a blinded independent review. According to Genmab, it will present also investigator-reviewed PFS and CR rate which will be numerically higher than Gazyva’s data. Safety profile also appears milder with Arzerra, but it is unclear how much weight is given to this aspect in light of the impressive efficacy.
Regardless of the Gazyva-Arzerra debate, investors’ focus should shift to daratumumab (anti-CD38), which represents Genmab’s most important growth opportunity. Genmab will present initial results from a combination trial for daratumumab and Revlimid. The abstract is scarce in details but it appears the combination is safe and active. A response rate below 80% should be regarded as disappointing.
The more intriguing CD38 data set will come from Sanofi’s CD38 antibody (SAR650984, licensed from Immunogen [IMGN]), for which Genmab’s investors should pay close attention. Although it is hard to compare SAR650984 to daratumumab based on the limited data in the abstract, the abstract has clear signs of activity in multiple myeloma. In addition, activity looks dose dependent with 4/9 (44%!) patients treated at the 2 higher doses achieving a PR. This is comparable to daratumumab’s response rate, but depth and durability of responses is unknown.
This is a positive for Immunogen, whose investors are looking for additional revenue generating assets beyond Kadcyla (T-DM1). For Genmab, SAR650984’s results suggest daratumumab will compete with other CD38 antibodies but they also validate CD38 as a target. (I previously discussed the CD38 landscape here). Sanofi already started a Revlimid combination trial for SAR650984 but did not disclose long term plans for the program. In order to be competitive, it must accelerate the development program as J&J (JNJ), Genmab’s partner, is putting a tremendous amount of resources behind daratumumab.
In contrast to prior expectations, Celgene/Morphosys (MOR.DE) will not present results for their anti-CD38 antibody, MOR202.
Array – Update on ARRY-520 and ARRY-614
Array Biopharma (ARRY) will present updated results for ARRY-520 in multiple myeloma and more interestingly, about the utility of AAG level as a patient-selection biomarker.
A study evaluating ARRY-520 alone or with dexamethasone demonstrated a response rate of 16% for both regimens with response duration of 8.6 months in the monotherapy arm. In patients with low levels of AAG in the blood, response rates were 23-24% vs. 0% in AAG-high patients. Results continue to suggest that AAG as a biomarker could identify a patient population for which approval can be obtained with a single arm phase II. Importantly, the abstract includes a fairly large sample size (82 patients), which should be considered more reliable than last year’s update (45 patients).
Acknowledging ARR-520’s efficacy, it is important to note that only half of the patients in the monotherapy arm were double-refractory (to Revlimid and Velcade). In addition, ARRY-520 does not look as active as CD38 antibodies and it also has a high frequency of bone marrow toxicities.
According to the abstracts for the Kyprolis and Velcade combinations, the two regimens clearly have activity but it is hard to tell whether ARRY-520 leads to a significant improvement. The Kyprolis abstract reports a response rate of 37% (7/19) and the Velcade abstract reports a response rate of 31% in 13 patients who were given higher doses of the drugs. These response rates are numerically superior to what could be expected with monotherapy Kyprolis and Velcade but the difference does not appear dramatic (~10-15% absolute improvement).
Array will also present data for a new formulation of ARRY-614 in myelodysplastic syndrome (MDS). The abstract discloses proof of target inhibition in the bone marrow and signs of efficacy as defined by a hematologic Improvement in 12/54 evaluable patients. At ASH, ARRY-614’s potential may become apparent with additional data for clinically relevant doses and guidance from Array on regulatory strategy for the drug based on interaction with the FDA.
Ambit – As expected, strong AML data
Ambit (AMBI) will present important data for its Flt3 inhibitor in AML as single agent and in combination with standard treatment regimens. The monotherapy data will shed light on quizartinib’s efficacy at lower doses (30/60 mg) and whether these doses are associated with less side effects (especially cardiovascular). The monotherapy data may be used for obtaining accelerated approval whereas the combinations will be the basis for a broad registration program.
In the monotherapy trial (76 patients), both doses induced a CRc rate of 50% with the vast majority of patients achieving CRi (incomplete hematologic recovery). 29%-37% of patients were bridged to stem cell transplant, which is considered the ideal therapeutic option in AML. This data set is in line with expectations and despite the low number of full CRs, quizartinib is still the most promising AML agent in development. Nevertheless, it is still unclear whether the results are sufficient for accelerated approval (discussed here).
When compared with these results, Epizyme’s recent phase I update in AML looks unimpressive.
Stemline – Robust activity in rare tumor
Stemline (STML) will present updated results for SL-401 in BPDCN (blastic plasmacytoid dendritic cell neoplasm), a rare cancer type with no approved treatments. The abstract includes 5 evaluable patients, all of whom achieved a response including 4 who achieved a CR after a single treatment cycle. SL-401’s activity coupled with the unmet need and rarity of BPDCN implies a very high likelihood of approval based a single arm phase II. The main issue with this drug is whether it can be given chronically, due to immunogenicity.
Portfolio holdings – November 17th, 2013