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Alpine Immune Sciences, Inc. (ALPN)

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  • i
    integrityfirst
    matt...our view on Merck collaboration is constructive. we like the neon2 trial which allows company to treat patients who are eligible for immune checkpoints and who have not been treated with immune checkpoints. our view is alpn 202 will prove effective in patients, who have stronger immune systems than neon1 patients... we do not think merck gave us any money; only the drug. the dosage ladder will be much quicker than neon1. the fact we are combined with keytruda may mean that we atteact patients quickly.
  • a
    al
    Alpine Immune Sciences, Inc. (NASDAQ: ALPN), a leading clinical-stage immunotherapy company focused on developing innovative treatments for cancer and autoimmune/inflammatory diseases, announced today a clinical trial collaboration and supply agreement with Merck. This collaboration will evaluate the safety and efficacy of Alpine’s ALPN-202, a first-in-class conditional CD28 costimulator and dual checkpoint inhibitor, in combination with Merck’s anti-PD-1 therapy KEYTRUDA® (pembrolizumab), the first anti-PD-1 therapy approved in the United States. The clinical trial, NEON-2, began dosing study participants in June 2021.
  • i
    integrityfirst
    Matt and Sam
    What we received from NEON 1 cancer trial at ASCO was very good safety, great early stage immunology including pk/pd/Treg/Memory cell etc., and "some" very early stage efficacy data suggesting very early stage efficacy. The clinicaltrials.gov Alpine submissions involving both ALPN 101 Phase 2 and NEON 2 (ALPN 202) Phase 1, indicate both trials starting next month, in July 2021 ... Further corroboration of the TWO start dates being July, have been voiced by management a) They have guided towards a mid year ALPN 101 Phase 2 start date, b) the June 2021 dated, ALPN corporate presentation on ALPN website under Events has a time "bar chart" for ALPN 101 and NEON 2, both indicating about July, c) Stanford Peng stated in the investor talk coinciding with ASCO, that "they were presently working on starting the NEON 2 trial". Management is certainly aware that the best general strategy to take in informing Investors, is to underpromise and overdeliver. Thus when Management indicates, as they have, that the start dates for the two trials is July 2021, that they intend to hit those two July targets. This should immediately bring in 25mm (first chunk from Abbvie for ALPN 101 phase 2 launch) and should acquaint Investors with the details of NEON 2 (combo ALPN 202 cancer trial phase 1). The devil is in the details always. I suspect NEON 2 will involve an FDA approved PD1 checkpoint inhibitor. Further I believe management when it says the dosing protocol will be relatively short. Further I suspect NEON 2 trial will produce fairly powerful, relatively quick results, in a patient population that is close to "treatment naive" with advanced stage cancer, likely in cancer indications which can be helped by the combination of ALPN 202 and the selected PD1 checkpoint inhibitor... We are adding to an already large position.
    Bullish
  • M
    Matt
    Dr. Goldberg defects from IOVA, a company 5-10 times the size of ALPN, to become the chief medical officer. I surmise that she has already seen the latest 202 data. She has left TIL; LN-144/145 in favor of ALPN 202. She took a 160,000 share option package with an exercise price of $10.29 (yesterday’s close). I would imagine she could have waited a week to sign on and get next weeks closing price as the exercise price. She knows more than we do. Why sign on before ASCO?

    Here is a poster representing some of what she left behind:

    https://www.iovance.com/wp-content/uploads/SITC-2020-ePoster_IOV-COM-202_HNSCC-Cohort2A_26Oct2020_final_FINAL.pdf
  • B
    Bilo_Sellhi
    Friday, June 4 at 7:00pm EDT
    Alpine Immune Sciences, Inc. (NASDAQ:ALPN), a leading clinical-stage immunotherapy company focused on developing innovative treatments for cancer and autoimmune/inflammatory diseases, announced presentation of initial data from NEON-1, the company’s Phase 1 clinical trial of ALPN-202, a conditional CD28 costimulator and dual checkpoint inhibitor, at the American Society of Clinical Oncology (ASCO) Virtual Annual Meeting. NEON-1 is a first-in-human, dose escalation and expansion study of ALPN-202 monotherapy in advanced malignancies.
    Presentation highlights include:

    • ALPN-202 has been generally well-tolerated as of the data cutoff date. The most common treatment-related adverse events have included immune-related toxicities, particularly cutaneous reactions.
    • Although most enrolled participants have had tumors considered classically non-responsive to immunotherapies, 61% (14 of 23 evaluable) appeared to derive clinical benefit as defined as a best outcome of stable disease or better, as of the data cutoff date. One of these participants, with metastatic colorectal cancer, achieved an unconfirmed partial response.
    • Dose-dependent pharmacokinetics and pharmacodynamics have been observed, accompanied by expansion of circulating CD4+ T cells with upregulation of the ICOS activation and Ki-67 proliferation markers. An expansion of central memory T cells, and a downregulation of regulatory T cells, were also observed.
    "These data represent, to our knowledge, the first demonstration of safe, controlled CD28 agonism in humans, with measurable physiological consequences," commented Dr. Stanford Peng, Alpine’s President and Head of Research and Development. "The circulating T cell changes are particularly exciting and consistent with the expected biology of CD28. Together with the early suggestion of clinical benefit for some cancers not traditionally considered immune-responsive, these findings strongly encourage us to further develop ALPN-202."
  • M
    Matt
    Management, please...no more good news. Every time a positive report/merger/update comes out, this drops 5%. Stop being so good at your job and maybe the sp will start going up again.
  • n
    nikit2h
    Another dilution: sale $75 mln stock
  • S
    Sam
  • i
    integrityfirst
    ALPN for us this is a hold, and we do not lose sleep over recent price decline. We have seen no evidence that our fundamental projection for a 2-10 B $ market cap in 2 years, OR LESS, will not be met. Yes, ALPN 202 EARLY data was not persuasive. However the results were involving an ultra difficult patient base, and most patients had not received 3 mgs./kg. The company on March 18th announced ALPN participation in recent ASCO AND the NEON2 trial. The data cutoff for ASCO was mid February. Thus we now have 4 more months of data. In our "speculative" view, Management made the decision to release early data at ASCO because Management wanted to execute NEON2 {trial just initiated), which involves "locally advanced" solid tumor patients. The definition of "locally advanced" included Stage 2 and 3. NEON1 trial did not, to my knowledge, involve Stage 2 patients. Certainly NEON1 patients are generally in worse shape, evidenced by NEON1 patients averaging 3.9 cancer regimens prior to trial. Moreover, 72% of NEON1 patients had not received immunotherapy as for these patients, immunotherapy was NOT a recommended therapeutic regimen. My group expects Alpine, within 6 months, will have some favorable patient data to share in specific indications from either, or both, NEON1 and NEON2. The company received enormous validation from Abbvie again who coughed up another 40 mm (in addition to original 65) upon the announcement of first patient dosed, in ALPN 101, Phase 2. Fourth quarter, after the Talitacicept phase 3 data release, ALPN will launch a Phase 1 ALPN 303 trial, in lupus. Management has stated that ALPN does not fail to share information about ALPN efforts in ALPN 202, and ALPN 303, with partner, Abbvie. ALPN has forecast the remaining 30 mm from Abbvie to ALPN will take place within 11 months. Of course we forecast a ALPN 101 Phase 2 victory, thus believe Abbvie will execute its 75mm option agreement. There are 700mm more in biodollars after that, plus royalties. The market is not valuing early stage clinical pipelines very highly. Until, we see evidence to the contrary, we will add to a large position, when appropriate. This company has many shots on goal. Eventually, even one success will make this company worth MANY multiples of current price. Could it take 3 years? Yes. Might it take a year? Yes. We will see. In the meantime, investors should sleep comfortably with this one, for the long term.
    Bullish
  • M
    Matt
    Down 5% on 3x normal volume....no bueno.
  • M
    Matt
    https://www.google.com/amp/s/seekingalpha.com/amp/news/3698841-alpine-immune-sinks-on-disclosure-of-common-stock-offering-by-selling-shareholders

    It is amazing how poorly covered this company is in the investment community.

    This guy at seeking alpha takes the cake so far.

    The fact is that Alpn has always wanted to present 202 data at ASCO. They barely got their foot in the door with the data they had in February. They wanted ASCO badly enough that they went for it with early data, realizing that they could completely update the data at the meeting itself.

    The 30% run up early this week was in anticipation of the abstract and what it may include for evidence that ALPN may have a blockbuster. Again, most astute investors realized that ALPN barely got its foot in the ASCO door.

    But they did get it in.

    Now, Alpn has set the stage for a full download on June 4th. They have even set up an investor event. Does it seem like they are being bashful about the therapeutic dose results?

    The fact remains that this is still primarily a safety study. These patients have failed early lines of therapy. It is possible that many of them have low PD-L1 expression tumors, resulting in failure of the PD-1 blockers.

    If Alpn actually shows a significant preliminary clinical benefit (PR+SD) in this population- that would be incredible news.

    Now, we know so far, dosage of 0.3mg/kg or higher led to stable disease in 4 out of 4 evaluable patients.

    That is scant, but VERY promising in this patient population.

    The price action should bounce off the trend lines of the past 5 months.

    What do you think is going to happen to the price as we approach June 4th?

    Too much going on to stay short here. Cover up now before it’s too late shortie.
    After a rise of ~30.9% over the past four days, Alpine Immune Sciences < > has lost more than a tenth in value today in apparent reaction to a...
    After a rise of ~30.9% over the past four days, Alpine Immune Sciences <<ALPN>> has lost more than a tenth in value today in apparent reaction to a...
    www.google.com
    Bullish
  • S
    Sam
    I agree the trial is progressing very nicely. Considering that not one of the patients in this data set had received a therapeutic dose (3mg/kg), I'm pleasantly surprised that any efficacy was observed, let alone a partial response (tumor shrinkage). Since this data is only thru January, I expect the June 4 ASCO update will draw a LOT of attention to ALPN-202 which should certainly help speed enrollment in this important trial, as well as generate interest from the potential large Pharma owners of the seven FDA approved checkpoint inhibitors (Keytruda, Imfinzi,etc.) whose drug we will be using in combination in the NEON-2 trial later this year. VERY exciting to own shares in this cutting edge company. I also hope that we will soon hear about plans to do a combination trial with 202 and chemotherapy. Recall that preclinical studies showed that 202 used in combination with Oxaliplatin increased its' TGI (tumor growth inhibition) form 41.2% to 98.6% as shown here in fig. 5. It's a very exciting time to be a stockholder in this cutting edge company as it future unfolds.
  • i
    integrityfirst
    OP0039 (2021)ALPN-303, AN ENHANCED, POTENT DUAL BAFF/APRIL ANTAGONIST ENGINEERED BY DIRECTED EVOLUTION FOR THE TREATMENT OF SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) AND OTHER B CELL-RELATED AUTOIMMUNE DISEASESS. R. Dillon1, L. S. Evans2, K. E. Lewis1, J. Yang3, M. W. Rixon4, J. Kuijper5, D. Demonte5, J. Bhandari4, S. Levin2, K. Kleist1, S. Mudri1, S. Bort2, D. Ardourel5, M. A. Seaberg6, R. Wang6, C. Gudgeon1, R. Sanderson6, M. F. Wolfson4, J. Hillson3, S. L. Peng31Alpine Immune Sciences, Translational Sciences, Seattle, United States of America2Alpine Immune Sciences Inc, Immunology, Seattle, United States of America3Alpine Immune Sciences Inc, Clinical Development, Seattle, United States of America4Alpine Immune Sciences Inc, Protein Therapeutics, Seattle, United States of America5Alpine Immune Sciences Inc, Protein Engineering, Seattle, United States of America6Alpine Immune Sciences Inc, Bioanalytical Sciences, Seattle, United States of AmericaBackground: BAFF and APRIL are TNF superfamily members that form #$%$ and heteromultimers that bind TACI and BCMA on B cells; BAFF also binds BAFF-R. BAFF and APRIL support B cell development, differentiation, and survival, particularly for plasmablasts and plasma cells, and play critical roles in the pathogenesis of B cell-related autoimmune diseases. In nonclinical models, inhibition of either BAFF or APRIL alone mediates relatively modest effects, whereas their co-neutralization dramatically reduces B cell function, including antibody production. Fc fusions of wild-type (WT) TACI (e.g. atacicept and telitacicept) target both BAFF and APRIL and have demonstrated promising clinical potential in e.g. systemic lupus erythematosus (SLE) and IgA nephropathy but have not yet clearly exhibited long-term and/or complete disease remissions.Objectives: To generate a dual BAFF/APRIL antagonist with inhibitory activity superior to WT TACI and BCMA and with the potential to improve clinical outcomes in B cell-mediated diseases.Methods: Our directed evolution platform was used to identify a potent variant TNFR domain (vTD) of TACI that exhibits significantly enhanced affinity for BAFF and APRIL as compared to WT TACI; this TACI vTD domain was fused to a human IgG Fc to generate the therapeutic candidate ALPN-303. ALPN-303 was evaluated for functional activity in: 1) human lymphocyte assays, 2) the NOD. Aec1Aec2 spontaneous model of Sjogren?s syndrome (SjS), 3) the bm12-induced mouse model of lupus, 4) the (NZB/NZW)F 1 spontaneous model of lupus, and 5) preclinical rodent and cynomolgus monkey pharmacokinetic/pharmacodynamic studies.Results: ALPN-303 inhibited BAFF- and APRIL-mediated signaling in vitro in human lymphocyte assays, with significantly lower IC 50 values than WT TACI-Fc and belimumab comparators. In all mouse models evaluated, administration of ALPN-303 rapidly and significantly reduced key lymphocyte subsets including plasma cells, germinal center B cells, and follicular T helper cells. ALPN-303 significantly reduced autoantibodies and sialadenitis in the spontaneous SjS model, inhibited glomerular IgG deposition in the bm12-induced model of lupus, and potently suppressed anti-dsDNA autoAbs, blood urea nitrogen levels, proteinuria, sialadenitis, kidney lesions, and renal immune complex deposition in the NZB/W lupus model. As compared to WT TACI-Fc, ALPN-303 exhibited higher serum exposure and significantly and persistently decreased titers of serum IgM, IgG, and IgA antibodies in mice and cynomolgus monkeys ( Figure 1 ).Figure 1.ALPN-303 induces more potent suppression, as compared to WT TACI-Fc, of serum immunoglobulins following a single 9 mg/kg IV infusion (on Day 0; arrows) in female cynomolgus monkeys.Conclusion: ALPN-303 is a potent BAFF/APRIL antagonist derived from our directed evolution platform that consistently demonstrates encouraging immunomodulatory activity and efficacy in vitro and in vivo , superior in preclinical studies to anti-BAFF antibody and WT TACI-Fc. This novel Fc fusion molecule demonstrates favorable preliminary developability characteristics, including higher serum exposures and more potent immunosuppressive activities, which may enable lower clinical doses and/or longer dosing intervals than WT TACI-Fc therapeutics. ALPN-303 may thus be an attractive development candidate for the treatment of multiple autoimmune and inflammatory diseases, particularly B cell-related diseases such as SLE, SjS, and other connective tissue diseases. Preclinical development is underway to enable the initiation of clinical trials later this year.Disclosure of Interests: Stacey R. Dillon Shareholder of: Alpine Immune Sciences, Bristol Myers Squibb, Employee of: Alpine Immune Sciences, Bristol Myers Squibb, Lawrence S. Evans Shareholder of: Alpine Immune Sciences, Employee of: Alpine Immune Sciences, Katherine E. Lewis Shareholder of: Alpine Immune Sciences, Employee of: Alpine Immune Sciences, Jing Yang Shareholder of: Alpine Immune
    Bullish
  • i
    integrityfirst
    The more shorts the better! For "investors", pay attention to the pipeline. No time to go into it now but look at Matt's posts and my posts and more importantly listen to the 3/17, and 3/18 management podcasts published under events on the ALPN website. ALPN submitted the updated data set to ASCO on March 18th (to be released by ASCO on June 4th), according to ASCO guidelines under ASCO key dates. Therefore the statements which management makes on 3/18 and 3/17 were stated when management had the full knowledge of the data set which we will see on June 4th. So when Peng says on March 18th, paraphrasing closely, "we are encouraged by the analysis of the data to date", that is a meaningful statement. When Gold says " we know we do have a biologically active molecule" on March 18th, that is a meaningful statement. Remember the June 4th results relate to a refractory population who have failed other cancer drugs, including in some cases, other checkpoint inhibitors. Thus if ALPN 202 demonstrates as little as a 15% ORR, that would be remarkable. All pushback is invited. Nobody has a stranglehold on truth!
    Bullish
  • S
    Sam
    I'm way long here and share Integrityfirst's relentless optimism, but I see that there are 667,000 shares short as of April 30. With the NEON -1 trial first data readout for potential blockbuster ALPN 202 about to be revealed in less than 3 weeks at perhaps the world's premier cancer conference, ASCO, I'm very curious why anyone would be comfortable holding a short position at this time. If the news is bad, I could certainly see a 50-60% drop in the stock price, whereas with very good data I wouldn't be surprised to see a triple in the stock price within 5 trading days of the news. If the data suggests that with continued treatment, 202 is on track to confirm the preclinical mouse study in colon cancer where 73% of the mice had complete responses (complete eradication of all tumors) versus 18% with FDA approved checkpoint inhibitor Durvalumab (AstraZeneca's Imfinzi), I think a market cap of $1 billion ($40/share) would be justified pretty quickly. With the announcement this week of the new $150 million shelf offering just prior to the coming data readout as well as CEO Gold and President Peng's repeated recent conference presentation, multiple statements that they like the 202 trial results that they are seeing so far (Neon-1 is a non-blinded, open label trial where every patient gets the 202 drug), it would appear likely if you believe direct statements from the top two officers of the company, that good news should be expected at ASCO. This week's upward trading momentum is also highly positive as small cap biotechs announcing possible dilutions usually suffer significant drops in the share price. So, sincerely, to anyone out there that would like to present your short thesis, I would be very appreciative to hear your thoughts, because if I'm wrong here it certainly wouldn't be the first time.
  • i
    integrityfirst
    Matt, Sam and others:
    ALPN 202 NEON1, Phase 1, trial, is progressing very nicely.
    https://meetings.asco.org/abstracts-presentations/196054
    The drug is proving itself to be safe, and effective, even at the low doses, which were administered as
    of February 17th, the date ALPN made a data submission to ASCO. The June 4th ASCO presentation will disclose data relating to higher doses, including, 3 mgs/kilogram, which is the likely therapeutic dose, and 10 and 20 mgs per kg..
    I am bullish on 202, 101, 303, and the recently announced NEON2 combination trial in "early", treatment naive, cancer patients.
    AS ALWAYS INVITE COUNTER POINTS OF VIEW...
    Bullish
  • i
    integrityfirst
    ALPN presently appreciated. we are adding. why? we are bullish b/c 1) expect favorable NEON 1 safety/efficacy/dosage results June 4 2) expect ALPN 202 phase 2 launch July and first Abbvie tranche 25mm june or July 3) expect NEON 2 phase 1/2 combo trial second half. 4) expect ALPN 303 Eular June 2nd presentation to expand on quick pathway for best in class 303. 303 trial begins 4th quarter.
  • B
    Bilo_Sellhi
    ASCO abstract: Background: Strong preclinical rationale has emerged for combining checkpoint inhibition (CPI) with T cell costimulatory agonists, particularly CD28, a critical T cell costimulatory molecule recently recognized as a key target of checkpoint inhibition. ALPN-202 is a variant CD80 vIgD-Fc fusion that mediates PD-L1-dependent CD28 costimulation and inhibits the PD-L1 and CTLA-4 checkpoints. It has demonstrated superiority to CPI-only therapies intumor models, while demonstrating favorable safety in preclinical toxicology studies.
    Methods: This is a cohort-based, open-label dose escalation and expansion study of ALPN-202 in adults with advanced solid tumors or lymphoma (NCT04186637). Subjects with cancers refractory to standard therapies (including approved CPIs), or cancers without available standard or curative therapy are eligible. After two planned single-subject cohorts, a standard 3+3 dose escalation has been implemented with two dose schedules in parallel, Q1W and Q3W. Objectives include evaluation of safety and tolerability, PK, PD and preliminary anticancer activity of ALPN-202. Disease assessments are evaluated by RECIST v1.1 for solid tumors or by Lugano Classification for lymphoma.
    Results: As of January 2021, 20 subjects with advanced malignancies have received ALPN-202. Dose-dependent PK and target saturation have been preliminarily observed. So far, ALPN-202 has been well tolerated at dose levels ranging from 0.001 to 1 mg/kg weekly, with no DLTs. Low-grade skin toxicities (grade 1-2 rash) have been observed in 4 subjects (20%). Among 11 evaluable subjects, an unconfirmed partial response has been observed in one subject with colorectal carcinoma, while stable disease has been observed in 5 subjects with colorectal carcinoma, mesothelioma (2), cholangiocarcinoma, and renal cell carcinoma -- for a preliminary clinical benefit (PR+SD) rate of 100% (4/4) at dose levels of 0.3 mg/kg and higher, or 54% (5/11) overall (table). The meeting presentation will update this data, which is expected to include the conclusion of Q1W dose escalation, as well as immune correlates.
    Conclusions: First-in-human dose escalation with ALPN-202 has been well tolerated at doses capable of engaging CD28 costimulation in vivo in association with dual PD-L1/CTLA-4 checkpoint inhibition, with early signs of anti-tumor activity. These findings suggest that CD28 agonism can be safely achieved in humans, and further suggest that dose expansion with ALPN-202 is warranted to assess the relevance of controlled CD28 costimulation as a novel approach to cancer immunotherapy. Clinical trial information: NCT04186637
  • E
    E
    as of May 14 there were 29k more shorts than last month. total 630k or 6.26% of float according to Yahoo. what are they thinking?
  • i
    integrityfirst
    Good post Sam on the pre clinical ALPN 202 work on combination therapies. Evidently you, like us, pay close attention to the plethora of posters available under Scientific publications on the Alpine website. My group is very happy with the data set released yesterday at ASCO. The more one studies it, the more impressed one is. An important fact is that at .1 mg/kg, the company generated 4 "stable disease" out of 4 patients. Remember that therapeutic dose is estimated to be 3 mgs/kg, or 30x more. Current positive things and catalysts include 1) "imminent" news on ALPN 101 which likely means Phase 2 start in the next month 2) mid year receipt of first 25mm from Abbvie 3) June 4th 7 p.m. Eastern ASCO 202 presentation/question and answer 4) ALPN 303 poster at EULAR in early June--303 trial start date fourth quarter 5) NEON 2 combination trial with ALPN 202 begins this year 6) Peng and Gold correctly characterized the May 19th ASCO ALPN 202 dataset having earlier stated in March on several published podcasts that ALPN Mgt. was "very encouraged by the analysis' of the data seen on the NEON 2 trial". In short, we hope the stock continues to underperform as we continue to add. As we did today!
    Bullish